Human Parathyroid hormone (PTH) is an 84 amino acids residue polypeptide sequence as shown in SEQ ID NO: 1 (Keutmann. H T, Sauer. M M, Hendy. G N, O'Riordan. J L H, Potts. J T. Complete amino acid sequence of human parathyroid hormone, Biochemistry 17; 1978; 5723), which acts as the most important regulator of calcium homeostasis in the human body through its direct action on bone and kidney. Recent reports and studies in humans with certain analogs of PTH have demonstrated an anabolic effect on bone (Podbesek R, Edouard C, Meunier P J, Parsons J A, Reeve J, Stevenson R W, et al. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology 1983; 112:1000-6), and have leaded much interest in its use for the treatment of bone disorders.
PTH (1-34), PTH (1-31), and PTH (1-38) exhibits full biological activity of the full-length PTH(1-84) in osteoblasts. In recent years many methods have been investigated for the administration of PTH to the treatment in clinical trials (Neer R M, Arnaud C D, Zanchetta J R, Prince R, Gaich G A, Reginster J-Y, Hodsman A B, Eriksen E F, Ish-Shalom S, Genant H K, Wang O, Mitlak B H. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. Engl J Med 2001; 344:1434-41). A recent reported method emphasized the oral administration of PTH (1-34) showed biologically active. However, the bioavailability of PTH is only 5% and 2.1%, in comparison to subcutaneous administration (Leone-Bay A, Sato M, Paton D, Hunt A H, Sarubbi D, Carozza M, Chou J, McDonough J, Baughman R A. Oral delivery of biologically active parathyroid hormone. Pharm Res 2001; 18(7):964-70). On the other hand, the pulmonary route has shown 40% and 34% bioavailabilities of PTH (1-34) by means of intratracheal instillation or inhalation of dry powders, respectively (Codrons V, Vanderbist R, Verbeeck R K, Arras M, Lison D, Preat V, Vanbever R. Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats. J Pharm Sci 2003; 92(5):938-50). In addition to that for intermittent PTH delivery include programmed administration by osmotic pump and pulsatile transdermal administration (Suzuki Y, Nagase Y, Iga K, Kawase M, Oka M, Yanai S, Matsumoto Y, Nakagawa S, Fukuda T, Adachi H, Higo N, Ogawa Y. Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PYH (1-34). J Pharm Sci 2002; 91:350-61). Both of these methods showed equivalent anabolic actions of PTH on bone like subcutaneous administration. Human PTH (1-38) has also shown similar results. There is relatively little work focusing on local delivery of PTH. Notably, these few studies indicated that PTH administered locally via a direct gene delivery which was found to be beneficial in the treatment of bony defects (Bonadio J, Smiley E, Patil P, Goldstein S. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 1999; 5: 753-9).
PTH (1-34), also called teriparatide, is commercially available in market under the brand name FORTEO® manufactured by Eli Lilly, Indianapolis, Ind., for the treatment of osteoporosis in postmenopausal women with high risk of fracture (Zhang, S, Eli Lilly and company, Indianapolis, Iowa (US). U.S. Pat. No. 6,590,081-B1). This drug is administered by once in daily subcutaneous injection of PTH (1-34) formulations (acetate buffer, mennitol, and m-cresol in water, pH 4). However, many people had adverse response to injections, and thus become non-compliance with the prescribed dosing of the PTH.
Recently, the Applicant found that PTH (1-34) acts on articular chondrocytes to suppress their terminal differentiation, and it can also suppress papain-induced osteoarthritis in rats (Chang. J K, Chang. L H, Hung. S H, Wu. S C, Lee. H Y, Lin. Y S, Chen. C H, Fu. Y C, Wang. G J, Ho. M L, Arthritics and Rheumatology 2009; 60; 3049-3060). But, the treatments requires the administration of drug once in 3 days, which makes more sufferings and inconvenient for patient undergoing treatment. Thus, there is a need to develop a new controlled releasing carrier formulation of a parathyroid hormone peptide in order to reduce the patient suffering and that has suitable bioavailability such that therapeutic level can be achieved for effective treatment of PTH related disorders.
However, in general protein and peptide are unstable in the gastrointestinal tract, have short half-lives, and bio-availability of their aqueous formulations are very low (Fix, J A. Oral controlled release technology for peptides: status and future prospects, Pharm. Res. 1996 December; 13(12):1760-4). These properties make challenge their effective usage in clinical applications.